Platinum diamine complexes are well known in the art because of the tremendous success of cisdiamminedichloroplatinum(II) (cisplatin) for the treatment of ovarian, testicular, head and neck, and other forms of cancer. In addition, cisplatin is used in conjunction with other therapeutic regimens including radiation therapy. This platinum chemotherapeutic mediates apoptosis at the G2 phase of the cell cycle predominantly through transcription inhibition and through replication inhibition processes, especially at high doses. Covalent bonding to DNA through the N7 sites of guanine and adenine bases, both by intra- and inter-strand modes, is generally believed to be the key molecular event in transducing a cascade of cellular responses leading to apoptosis.
Although cisplatin is highly effective, it exhibits renal, nephro-, and neuro-toxicities. Moreover, many patients develop resistance to cisplatin treatment over time and are therefore not cured by cisplatin treatment. Two other FDA-approved platinum drugs, carboplatin (diammine-1,1-dicarcarboxylatocyclobutane-platinum(II)) and oxaliplatin (diammine-oxalatoplatinum(II)), are also believed to function in a similar manner to that of cisplatin. Carboplatin is especially effective towards cisplatin-resistant tumor cells, but relatively high doses are required to effectively treat patients who are resistant to cisplatin. Such high doses also have associated toxicities.
Many new platinum amine complexes have been synthesized and tested for their anticancer activities. However, only a few of these complexes (some of which are listed in FIG. 14) have exhibited promising results. These new complexes contain a variety of replaceable nonamine ligands, as well as nonreplaceable amine ligands that are believed to be important for DNA binding and cellular uptake. Generally, these and other relevant platinum ammine complexes known in the art are synthesized by the process used for preparing cisplatin, namely where tetrachloroplatinate (PtCl42−) receives amine ligands to become PtCl2(amine/diamine). Starting with the tetrachloro complex generally provides other products, and so PtI42− can also be used to ensure high yield and purity of the cis isomer, followed by conversion of PtI42− to PtI2(amine/diamine) and then into PtCl2(amine/diamine). In converting PtI2(amine/diamine) to PtCl2(amine/diamine), the di-iodo complex is converted to diaqua complex by treating the former with two equivalents of silver nitrate or other soluble silver salts at low pH. The resulting diaqua complex readily reacts with potassium chloride or hydrochloric acid to yield the dichloro complex of interest. In general, the platinum complexes of interest are synthesized from the corresponding diaqua complex at a low pH to introduce the replaceable ligands since dimerization or polymerization of the diaqua complex takes place rapidly at higher pH, yielding undesirable products.
Instead of replaceable chlorine ligands, platinum amine complexes in the art also have nitrogen, sulfur, carboxylate, and phosphonate as replaceable ligands. However, one characteristic of those complexes showing the most promise for treating cancer is a replaceable hard base ligand coordinated to platinum (a soft acid). Examples of such hard-soft combinations that have displayed excellent anticancer properties are carboxylato, carbonato, phosphonato platinum complexes.
Despite tremendous efforts to replace cisplatin with more effective chemotherapeutics, platinum (II) and platinum(IV) complexes with phosphates as the replaceable ligands have remained largely unexplored. This is primarily due to the fact that early work on platinum(II) phosphato complexes usually resulted in phosphate-bridged dinuclear complexes. Despite reports of excellent anticancer properties of some dinuclear phosphatoplatinum(II) complexes, further exploration of their applications were limited because of the poor solubility of these complexes in aqueous solutions. Although certain monomeric pyro- and triphosphate complexes are known in the art, such complexes are not suitable for pharmaceutical compositions because they undergo phosphate hydrolysis in moderately acidic solutions, resulting in insoluble dinuclear products (See U.S. Pat. No. 7,342,122 to Odani et al., describing a dimer of the monomeric complex am-2, which is described herein and in Bose et al., Inorg. Chem. 1985, 24, 3989-3996; see also, WO 2005/000858 to Odani et al., describing monomeric am-2 as a potential anticancer drug).
Therefore, there remains a need in the art for stable and effective alternatives to cisplatin and carboplatin for the treatment of cancers.